![]() These results show that proteolysis-inducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia. There was also an increased expression of the 19S regulatory complex as well as the ubiquitin-conjugating enzyme (E2 14k), and in myotubes a decrease in myosin expression was seen with increasing concentrations of proteolysis-inducing factor. In both myoblasts and myotubes protein degradation was accompanied by an increased expression of the α-type subunits of the 20S proteasome as well as functional activity of the proteasome, as determined by the ‘chymotrypsin-like’ enzyme activity. Protein degradation induced by proteolysis-inducing factor was completely attenuated in the presence of cycloheximide (1 μ M), suggesting a requirement for new protein synthesis. In myoblasts this followed a bell-shaped dose-response curve with maximal effects at a proteolysis-inducing factor concentration between 2 and 4 n M, while in myotubes increased protein degradation was seen at all concentrations of proteolysis-inducing factor up to 10 n M, again with a maximum of 4 n M proteolysis-inducing factor. In both myoblasts and myotubes protein degradation was enhanced by proteolysis-inducing factor after 24 h incubation. The mechanism of muscle protein catabolism induced by proteolysis-inducing factor, produced by cachexia-inducing murine and human tumours has been studied in vitro using C 2C 12 myoblasts and myotubes.
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